16-halomethylene steroids



United States Patent Office 3 16 IS-HALOMETHYLENE STEROIDS Fritz yon Werder and Klaus Briickner, Darmsiadt, Karl- Heinz Bork, Griesheiin, near Darrnstadt, and Harald Metz, Darmstadt, Germany, assignors to E. Merck Aktiengesellschaft, Darmstadt, Germany No Drawing. Filed June 5, 1962, Ser. No. 200,060 Claims priority, application Germany, June 8, 1961, M 49,291; July 8, 1961, M 49,608; Iuiy 20, 1961, M 49,747; July 27, 1961, M 49,842

12 Claims. (Cl. 260397.4)

The present invention relates to new anduseful steroids of the pregnane series.

It is an object of this invention to provide novel compounds having a valuable physiological activity as well as compositions containing these compounds together with pharmaceutically acceptable 'ercipients.

It is a further object of this invention to provide a new process for producing said compounds.

The new compounds of this invention include those represented by the Formula I wherein R designates hydrogen or a free or esterified hydroxyl CHaBi wherein R R R,, X and Y have the above meaning. likewise, the A 13 or A -derivatives thereof may be used.

3,151,661 Patented Dec. 15, 1964 The starting compounds of Formula II are readily available from the corresponding 16-methylene-17a-hy droxy steroids some of which are described in Tetrahedron Letters, No. 16, 1960, pp. 2132, or which may be obtained from the compounds described in South African Patent 264/6l by saponification of the 17macetoxy group and, if desired, by substituting a hydrogen atom in the ll-position by a hydroxyl or acyloxy group according to standard methods. By treatment with N- chloroor N-bromo succinimide, such l6-methylene-l7a hydroxy compounds are converted into the 16-bromoor 16chl0romethyl-l6a,l7a-oxidosteroids according to Formula II. Starting with the IG-bromomethyl compounds, the 16-fluoromethyl-l6,l7a-oxido steroids of Formula II are prepared by treatment with silver fluoride in acetonitrile or with potassium fluoride in diethylency According to the new process of this invention, a compound of Formula II is treated with hydrogen bromide in the presence of an inert organic solvent to form the corresponding 16-halomethylene-17d hydroxy steroid of Formula 111'.

or the A A- or n -derivative thereofwherein R R R and X and Y have the above significance.

Suitable inert organic solvents for this reaction are, for example, benzene, toluene, telrahydrofuran, acetone, chloroform, carbon tetrachloride, ether and dioxane, dioxane, or glacial acetic acid. Particularly high yields are obtained when using as solvent a mixture of ether and dioxane. The preferred range of the reaction temperature is from l0? C. .to the boiling point of the used solvent. The reaction times vary from $6 to 20 hours depending on starting material and temperature. Generally, the reaction mixture is refluxed for about 1 to 2 hours. Then it is concentrated and poured into water whereby the desired product is precipitated. It may be purified by recrystallization or by chromatographic methods.

It was highly surprising that evidently only hydrogen bromide is suitable for this reaction to prepare the 16- halo-methylene-l'la-hydroxy steroids of Formula III in high yields and without by-products. When using other acids, such as, for instance, hydrochloric or para-toluenesulfonic acid, the desired compounds are only obtained in poor yields andhave to be separated from various byproducts. This was complete y unexpected since 1611,1701- oxido-l6B-methyl steroids are known to be converted by treatment with any of these acids into the corresponding IS-methyIene-lh-hydroxy steroids without any ditficulties.

. otherwise the same.

To prepare the new compounds of this invention, the splitting of the lo-halomethyl-la,l7a-oxido steroids with hydrogen bromide is the main reaction and may be carried out at any desired reaction stage. Thus, it may be the final step in the preparation of the useful compounds of Formula I, or, likewise, an intermediate step which is followed by one or more further reactions well known in steroid chemistry.

For example, a hydroxyl group may be introduced into the ll-position of a lG-halontethylenel7tz-hydroxy steroid of the Formula III wherein R and Y are hydrogen by usual microbiological methods. All microorganisms suitable for such reactions may be employed, for example, fungi of the genera Cu'rvularia, Mucor, Stachylidium and Streptomyces' (introducing a hydroxyl group at the 11pposition) or fimgi of the genera Absidia, Cunninghamella, Fusarium, Mucor, Penicillium, Rhizopus (introducing a hydroxyl group at the Ila-position). The hydroxylation is efiected according to standard procedures. The startiug material is added to a culture of the microorganism which grows in a suitable nutrient solution at optimum temperature and with aeration. After to 48 hours, the ll-hydroxy steroid is isolated from the reaction mixture, preferably by extraction with a suitable organic solvent such as chloroform or methylene chloride.

The obtained ll-hydroxylated compounds may subsequeritly be oxidized to form the corresponding ll-keto steroids. For this oxidation, mild oxidizing agents are preferred. For example, chromic acid anhydride in glacial acetic acid or a miimrrc of chromic acid anhydride and pyridine or a mixture of sodium bichronrate, sulfuric acid and acetone maybe used. The ll-kcto steroids are isolated from the reaction mixture by extraction or by precipitation with water.

Furthermore, a double bond may be introduced at any reaction stage into the ll-positiou. The 1,2-dehydrogenation can be efiected chemically or microbiologically. As chemical dehydrogenation agents, there are particularly suitable 2,3-dicbloro-S,6-dicyano-benzoquinone or selenium dioxide.

when using selenium dioxide, an alcohol such as tbutanol, t-amyl alcohol, or ethyl acetate iscmployed as solvent. The reaction can be accelerated by the addition of small amounts of glacial acetic acid. Advantageously, the reaction mixture is refluxed for about 12 to 48 hours. The precipitated selenium is separated.

For a dehydrogenation with 2,3dichloro-S,6-dicyano benzoquinona'benzenc and dioxanc are particularly suitable as solvents.

For the microbidlogical 1,2-dehydrogenation, there can be used all themicroorganisms customary for this purpose. Badllus splza eficus var. fusiformis, Corynebacten'um simplex and Fusan'wn solazu are particularly suitable.

For the dehydrogenation, the starting material is added to a submerged culture of the microorganism employed which grows in 3. suitable nutrient solution at optimum temperature and with strongaeration in accordance with the customary methods of the fermentation art; Instead of growing cultrnes, suspensions of the microorganisms in butter solutions can also be used, the method being The course of the reaction is observed chromatographically and the fermentation solution extracted, for instants: with chloroform, after complete reaction of the starting material.

In some cases, 2 l-O-acylg compounds are converted into Zl-OI-I compounds in the course i a microbiological process as described above. i

To introduce a double bond into the 6,7-position, a compound of Formula III which is saturated in the 6- position is reacted with chloranil. One advisedly operates in a solvent having a boiling point of about 30 to 150 C. As solvents, the following are, for instance, suitable: alcohols, such as ethanol, tert.-butanol or terL-amyl alcohol, methyl acetate, ethyl acetate, dioxane, glacial acetic acid, benzene, tetrahydrofuran, acetone, etc.

The compounds of the Formula III wherein R is hydrogen can be converted at any desired reaction step into the corresponding ll-hydroxyl or Zl-acyloxy compounds. According to the most common method known in the art, the starting material is treated subsequently with an alkaline solution of iodine and with an alkali metal acylate, preferably potassium acetate. The 2l-acyloxy compound thus obtained may be saponified, if desired, to form the corresponding Zl-alcohol. The saponification is effected in the usual manner, for example, by an aqueous solution of sodium bicarbonate.

To prepare the 9a-fitl01'O-COIHPOUIldS of this invention, the usual sequence of reactions may be employed. For example, a compound of the Formula III wherein R and Y are hydrogen can be hydroxylated microbiologically at the ll-positio'n. Upon treatment with a dliydratiug agent, for example potassium acetate, the corresponding 9,1 l-dehydro compound is obtained which is converted into the 95,11,6-oxido compound with standard proce dures. Reaction with hydrogen fluoride results in the formation of the corresponding 9a-fluoro-ll18-hydroxy compound.

The ZI-position-hydroxyl group present in any of the molecules whether starting material, intermediate or produet may be readily esterified by standard methods. All acids or their derivatives are suitable which form physiologically acceptable esters. Among the large number of acids to be used, the following are named by way of illus tration: acetic acid, propionic acid, butyric acid, trimethyl acetic acid, t.-butyl acetic acid, cyclcpentylpropionic acid, pheuylpropionic and phenylacetic acid, capronic acid, caprylic acid, palmitic acid, undecylenic acid, benzcic acid, chloroacetic acid, diethylaminoacetic acid, aspartic acid, oxalic acid, succinic acid, phosphoric acid, sulfuric acid. In the event that the esterified Zl-lrydroxyl group is one derived from a dibasic acid, it is often advantageous to treat such esters with an alkali metal or alkaline earth metal hydroxide to prepare the corresponding salt. Such salts are especially useful because of their increased solubility in water.

To obtain compounds of the Formula I wherein R, is an acyl group, the corresponding lla-hydroxyl derivatives are acylated in accordance with known methods customary for tertiary hydroxyl groups. Preferably, a mixture of acetic anhydride and glacial acetic acid, including an addition of p-toluencsulfonic acid, is employed as acylating agent. For l'la-acyloxy derivatives of carboxylic acids of higher carbon content, such as propionic or capronic acid, the corresponding acids and acid anhydrides are used.

The products and methods in accordance with the present invention make it possible to provide the physiologically active valuable l6-halomethylene compounds of Formula I. The new compounds can be-uscd as therapeutic agents. The derivatives of the corticoid series possess an increased antiphlogistic activity which is tested according to'the method described by R. Hotovy et at. in

Archives Internationalcs de Pharmacodynamie et de Thrapie, vol. 111, p. 420 (1957). The new compounds of this invention belonging to the progesterone series exhibit an increased gestagenic activity. Some of them, particularly those substituted by a lla-acyloxy group, are characterized by extremely good oral elfectiveness. In the Clauberg test on rat: (cf. Ioumal of Physiology, vol. 83, p. (1934)) the new compounds were compared to known gestagenes.

The active compounds of this invention may be administered alone or in combination with acceptable pharmaceutical carriers, the choice of which is determined by the desired route of administration. They can be worked. up into all forms of application which are customary for pharmaceutical purposes, such as pills, tablets, drages, suppositories, emulsions, suspension or injection solutions. Usual adjuvants, fillers, solvents or solubilizers may be.

added if desired. In general, the pharmaceutical preparations contain from 1 to 100 mg. of the active ingredient.

The dosage of the compounds of the corticoid series is of approximately the same order as the dosage of prednisolone, and the compounds are useful to treat all types of pathological conditions often treated with prednisolone. Because of their great activity, the doses are sometimes even lower than those of prednisolone. As to the compounds of the progesterone type, these ones may be used for all indications of 17e-acetoxy progesterone or 1711- hydroxy-fia-methyl-progesterone. For instance, the substances are suitable as means for combating threatening abortion, for restoring the uterus nucous membranes or in functional uterine bleeding.

The following examples are given solely for illustration and are not to be construed as limitations of this invention. As will be recognized by those skilled in the art, there are many modifications of the processes for the preparation of the new compounds which are intended to be within the full spirit and scope of this invention. Especially, the sequence of the reaction steps may be varied largely, depending on the used starting materials and the desired product.

Example 1 El; 488 (ethanol); (or) 5" -44 (chlorofonn) (b) 10.6 of lechlommethylenei -hydro yb qs terone are allowed tostand overnight at room temperature with 796 ml. of glacial acetic acid, 159 nihof acetic anhydride and 15.9 g. of p-toluene sulfonic The reaction mixture is poured into water; the precipitate is filtered 0E, washed with water and dried. The crude prodnot is dissolved in benzene and filtered through alumina. H

The combined benzene eluates arecofientrated. The 16*:hloromethylene 4 pregnene-3,2 0-dione-17a-oll7- acetate is crystallized from-ether. Ml. 207-208", (11) --90.6 (chloroform); A 239 mp1, 3 i

1 Example 2 l 1.32 g. of 16B-chloromethyl-16a,l7a-oxido-d-pregnene- 21-ol-3,20dione-21-acetate are dissolved in a mixture of 40 ml. of dioxane and 40 ml. of ether. Upon addition of 5 ml. of an ethereal solution of hydrogen bromide (10% the sdlution is re uxed for minutes. The hair ture is concentrated to alf the volume and poured into water. The precipitated crystals are filtered 0E and recrystallized firom acetone. The 16-chloro-mefl1ylene-4 pregnene 1711,21 diol 3,20 dione 21 acetate melts at 156-157" C., A 240 m El? 434 (ethanol; 05 +105 (chloroform) Example 3 4.3 g. of 9a-fihoro-l6B-ch1oromethyl-16e,l7aroxido-4- pregnene-11B-ol-3,20-dione in 250 ml. of dioxane, 200 ml. of ether and 15 ml. of an ethereal hydrogen bromide solution (27.5%) are refluxed for 1 hour. The reaction mixture is worked up as described in Example 2. The 90: fluoro 16 chloromethylene 4 pregnene 115, 17a diol 3,20 dion is recrystallized from methanol. A 245) my,

6 Example 4 According to the method described in Example 2, 1.3 g. of 165 chloromethyl 1611,1711 oxido 1,4, pregnadiene-ll,B,2l-diol-3,20-dione-2l-acetate in ml. of dionane and 100 ml. of ether are refluxed for 1 hour with 3.5 ml. of an ethereal hydrogen bromide solution (27.5 Upon recrystallization from methanol, the pure 16 chloromethylene 1,4 pregnadiene- 113,17a, 2l=triol-3,20-dione-2l-acetate is obtained. M.P. 230- 231 C.; (00 ----31 (dioxane); A 242 m Elf... 358

Example 5 According to the method described in Example 1a, the 16 chloromethylene 4 pregnne 3,11,20-trionel'la,2l-ol-21-acetate is obtained from 16,8-chloromethyl- 1611,17 oxido 4 pregnene 3,11,20 trione 21 olacetate. Mi. 164-165" (3.; ((1); +133 (dioxane); m; 233 m hit... 372

Example 6 According to the method described in Example 2, the 16 chloromethylene hydrocortisone 21 acetate is obtained from 163 chloromethyl :,17or. oxido 4- Pregnene-BQO-dione-Il,21 diol-2l-acetate. M.P. 228- 230? (3.; (41);, +42 (dioxane); A 241 m Eli 392 Exainpie 7 (a) A solution of 2g. of 16fi-fl110l'0fl16ihYl-16uz,l7a oxido-progesterone in 67 m1. of dioirane and 67 ml. of other is refluxed for 1 hour with 15 ml. of an ethereal solution of hydrogen bromide (8%). The is concentrated to halfthe volume -arid poured into water. The pre cipitate is from acetone and yields pure 16- fluoroniethylene 17o: -hydroxypi'ogesteron. MP. 251- 252'? C.; @239 r E1; 509 (ethanol); (a)'i,-'+ io.s (chloroform) (b) 10.6 g. of 16 fluoromethylene 4 pregnene 17- ol-3,20 dione are allowed to overnight at room tempcrattnewith 79.6 ml. of glacial acetic acid, 15.9 ml. of acetic anhydride and 1.59 g. of p-to'ulene sulfonic acid. Then the mixture is pouredjnto water. The precipitate is filtered 0E, washed with water and dried. The crude product is dissolved in benzene and filtered through alumina. From the combined benzene 'eluat es, the 16 fluoromethylene 4 1 pregnene 17-0l-3,,-20 dione 17- acetate is obtained. M.P. 207-208 (chloroform); 1m 239.5 my,

(c) 2 g. of 16fluoromethylene-4-pregnene-1701-01-3 20- dione-l7-acetate are dissolved in 60 mL of tetlahydrofuran and refluxed for 10 hours with 1.6 g. of chloranil. The solution is diluted with water and extracted with chloroform. The combined chloroform extracts are washed with sodium hydroxide (2 N) and with water. The solvent is evaporated and the 16-fluoromethylene- +6-p'regnadiene-l7a-ol-3,20-dione-17-acetate is recrystallized from methanol. A 283 m E1; 7'95 Example 8 According to the method described in Example 7a, 1.32 g. iluoromethyl 1602,1702 oxido 4 pregnene- 2l-ol-3,20-dione-2l-acetate are treated with hydrogen bromide to form 16 fluoromethylene 4 pregnene 17m, 21 diol 3,20 dione 21 acetate. M.P. 200-202" C.; (11) +68 (chloroform); A 240 m Example 9 According to the method described in Example 4, 9aiiuoro l6 fluoromethylene 4 pregnene 1113,17:- diol-3,20-dione is obtained from 9a-fiuoro-16fl-fluoromethyl 16,l7a oxido 4 pregnene ll 8 ol 3,20- dione. A 240 m El; 397 Example 10 (:1) According to the method of Example In, the 16 chloromethylene-4-pregnene l7a-cl-3,20-dione is obtained from 16 chloromethyl 160:,17a oxido 4 pregnene- 3, 20-dione. M.P. 269-271 C.

(b) To a suspension of 6.5 g. of lfi-chloromethylene- 4-pregnene-17-ol-3,20-dione in 98 ml. of tetrahydrofuran and 59 ml. of methanol (9.8 g. of iodine and 98 g. of

" CaO are added in small portions within 3 hours. The

reaction mixture is poined into 2 l. of ice water containing 32 ml. of glacial acetic acid. The precipitate is filtered olf, dried and dissolved in 550 ml. of acetone. The solution is refluxed for 20 hours with 33 g. of potassium acetate. The acetone is partially evaporated under reduced pressure. Upon addition of water, the precipitate is filtered oil and refluxed for 2 hours with a mixture of 130 ml. of methanol, 3.25 g. of sodium pyrosulfite and 48.5 ml. of water. The reaction mixture is cooled and diluted with water. The precipitated 16- chloromethylene-4pregnene-l7a,2l-diol 3,20dione 21 acetate is filtered otf, dried and recrystallized from methanol. Ml. 156-157" C.; a -10.5 (chloroform); 7k 240 my,

' Ell. 434 (ethanol) (c) 12 g. of 16-chloromethylene-4-pregnene-17,21- diol-3,20-dione 21-acetate are dissolved in 960 ml. of methanol. Upon addition of 480 ml. of an aqueous potassium bicarbonate solution the mixture is refluxed for 3 hours. After cooling, crystals of l6-chloromethylene-4-pregnene17a21-diol-320-dione are obtained which are recrystallized from acetone. Ml. 205-207? C.; (40 +5 (chloroform); A 239240 m E11,, 463 (ethanol) (d) In a. fermentation vessel 15 l. of a nutrient solution containing 5% glucose, 0.1% yeast extract, 0.05% soybean meal, 0.3% NaNo 0.05% MgSOgH-LO, 0.1% KH PO 0.05% KCl, 0.001% FeSOy'lIfi-O are inoculated with 750 ml. of; culture of Fusarium sp. The culture grows with vigorous stirring and aeration at 28 C. After 24 hours, 5 g. of l6-chloromethylene-4-pregnene- 17,2l-diol-3,20 lione in 40 ml. dimethyI-formamide are added. As soon as the paper chromatogram no longer shows. any starting material, the culture is extracted three times with 10 l..of chloroform. The chloroform extracts are evaporated; th residue is washed with petroleum ether and the 1 oromethylene-l l-epi-hydrm cortisone recrystallized from acetone. A 241 m (e) 2 g. of l6-chloromethylene-1l-epi-hydrocortisone are dissolved in 10 ml. of yridine and 0.36 g. of glacial acetic acid anhydride. er standing for hours at room temperature, the solution is poured into water and extracted three times with chlorofo The chloroform extracts are neutralized with a 01 tion of NaHCO dried and evaporated in vacuo.- The amorphous residue of 16 chloromethylene-l l-epi-hydrocortisone-2l-acetate is used directly for the following oxidation.

(f) 2.7 g. of lS-chloromethylene-ll-epi-hydrocortisone-Zl-acetate are dissolved in 100 ml. of acetone and cooled to a temperature of 0 to 10 C. While stirring and cooling, 1.92 ml. of a solution of chromlc acid anhydried in sulfuric acid/water (1 ml. containing 0.25 g. of CrO are added at a temperature below 10 C. After stirring for 30 minutes, the reaction mixture is poured into Water and extracted with chloroform. The chloroform extract is washed to neutrality, dried and evaporated. The 16-chlorornethylene-cortisone-Zl-acetate melts upon recrystallization from ether/ acetone at 164 to 165 C. ((1);; +133 (dioxane); k 238 m Elf... 372

(g) 1 g. of l6-chloromethylene-c0rtisone-2l-acetate is refluxed with 25 mL-of methanol. To the boiling solution, a hot solution of 0.23 g. of sodium bicarbonate in 5 ml. of water is added. After boiling for 7 minutes, the solution is poured into 300 ml. of water and the precipitated crude product is filtered under suction. Upon recrystallization from acetone the pure l6-chloromethylenecortisone is obtained. A 238 m Elf... 380

(11) In a fermentation vessel 15 l. of a nutrient solution containing 0.1% yeast extract, pH 6.8, are inoculated with 1.5 l. of a culture of Corynebacterium simplex. The culture is grown with constant stirring and aeration at 28. After 4-8 hours, 7.5 g. of IG-chloromethylone-cortisone in 300 ml. of methanol are added. The dehydrogenation is controlled by paper chromatography and is usually finished after 10-14 hours. The solution is extracted three times with chloroform; the extracts are evaporated and the lfi chloromethylene-prednisone is recrystallized from acetone. A 239 mp,

Eli 405 Example 11 (a) 16 chloromethylene-4-pregnene-l7,21-diol-3,20- dione-Zl-acetate are prepared according to Example 2. M1. 156-157 C.

(b) According to the method described in Example 10c, the 16-chlorornethylene-4-pregnene-170:,2l diol 3, 20-dione-21-acetate is saponified to form 16-chloromethylene-4-pregnene-l1a,21-diol-3,20-dione.

(c) In a fermentation vessel 15 l of a nutrient solution containing 5% malt extract, 1% saccharose, 0.2% NaNO 0.1% K i-IP0 0.05% MgSO 0.05% KCl and 0.005% FeSO pH 7.0, are inoculated with 800 ml. ofa culture of Curvularia lunata. (Wakker) Boadiin. After growth for 24 hours at 28 C., 5 g. of l6'chloromethylene-17;l-diol-3,20-dione in 40 ml. dimethylformamide are added. Assoon as the paper chromatogram no longer shows any starting material, the culture is extracted three times with chloroform. The chloroform extracts are evaporated and the residue is chromatographed through silica'gel. The eluate running off with chloroform/ethyl acetate (1:3) contains l6-chloromethylene-hydrocortisone. F. 228 C.; (11),; +40 (dioxane).-

a 241-242 mp,

(d) 5 g. of lfi-chloromethylene-hydrocortisone are heated with 30 ml. of pyridine and 30 ml. of acetic' acid anhydride for 1 hour on the steam bath. The solution is poured into water and the precipitated 16-chloromethylene-hydrocortisone-2l-acetate is filtered ofi and recrystallized from acetone. M31 228-230 C.; (11) +l33 (dioxane),

E12,, 392. k 241 mp l is. 358

(e In a fermentation vessel 15 l. of a nutrient solution containing 1% yeast extract, pH 6.8, are inoculated with 0.5 1. of a culture of Bacillus sphaericus. The culture is grown at 28 and after 19 hours 7.5 g. of 16-ch1oromethylenehydrocortisone in 300 ml. of methanol are added. After 28-36 hours dehydrogenation is complete. The reaction mixture is treated according to Example 10h.

The 16-chloromethyleneprednisolone is recrystallized from acetone. M.P. 223-224 C. 34 (dioxane); A 241242 mg,

Eii 4.11 (ethanol) Example 12 (0) According to the method described in Example 110, the 16-fiuoromethylene-hydrocortisone is obtained from 16 fiuoromethylene 4 pregne'ne 17a,21 diel- 3,20-di0ne. M.P. 239-241 C.; (a) ;+85.4 (dioxane); h 241 my,

ll... 447 (d) g. or 1G-fiuoromethylene-hydrocortisone are heated with 30 ml. of pyridine and 120 ml, of acetic anhydride for 1 hour on the steam bath. The solution is poured into water, and the precipitated 16-fiuoromethylene-hydrocortisone-Zl-acetate is filtered oif and recrystallized from acetone. )r 241 III/1.,

(e According to the method described in Example lle the 16-fluoromethylene-prednisolone is prepared from 16 fluoromethylene-hydrocortisone. M1. 263- 264 0.; 00 +25 (dioxane); x 242 mu,

It is converted by usual methods into the corresponding 21-tert.-butylacetate. MP. 225226 C.; (u) ;+26.6 (chloroform), A 242-243 m Elfi 332 (ethanol) (2 According to the method described in Example 11:2 the 16-fluoromethylene-prednisolone-2l-acetate is prepared from 16 fiuoromethylene-hydrocortisone 21- aoetate. A 242 m Upon saponification, the l6-fiuoromethylene-prednisone is obtained.

Example 13 (a) According to the method described in Example In, the 6ot-methyl-16-fiuoromethylene-17e-hydroxy-progester one is obtained from 6oc-m3thyl-16-fll101OZ116tl1Yi-16oz,17o:- oxido-progesterone. x 241 m lli... 3 6

(11) According to the methods described in Examples 10b and c, the 6oc-methyl l6-fluoromethylene-4-pregnene- 17oc,21-diol-3,20-dione is obtained from 6a-methyl-16- fiuoromethylene 17b: hydroxy-prog'esterone. A 240 u,

(c) According to the method described in Example 110, the 6a-methyl-16-fluoromethylene-hydrocortisone is prepared from -6a-methyl-16 fluoroinethy1ene-4=pregriene- 17a,21-diol-3,20-dione. A 240.5 my,

(a!) According to the method described in Example 10h, the 6a-methyl-l6-fiuoromethylene-prednisolone is prepared from oat-methyl-l6-fludromethylene-hydrocorti sone. A x 242243 mg,

E12... 432 Example 14 According ot the methods set forth in Example 13, the 60:, methyl 16 chloromethylene-prednisolone is obtained trom a-methyl-l6,8-chloromethyl-16u,17a-oxido progesterone.

Example 15 According to the methods set forth in Example 13, the 60: fluoro-l6-fiuoromethylene prednisolone is obtained from 6u-fiuoro-lfi-fluoromethyl-160:,170; oxide-progesterone. k 242 m Ei g 415 Example 16 According to the methods set forthin Example 13, the 6a-fiuoro 16 chloromethylene-prednisolone is obtained from 6m fluoro-l6B-chloromethyl-16u,17a-oxido-progesterone. x 241 mu,

Ex 420 Example 17 (a) 16 -chloromethylene-17a-hydroxy-progesterone is prepared in accordance with the method of Example la. (b) The product obtained in Example 17a is subjected to the action of Curvularia lunata according to the procedure set forth in Example to form 16-chloromethylene-4-pregnene-1lB,l7ot-diol-3,20-dione. k 241 m (c) 16 chloromethylene-4-pregnene 116,17a-diol- 3,20-dione was treated in accordance with the method described in Example 1% to form 16-chloromethy1ene-4- pregnene 11,8,17a,21 triol 3,20-dione-21-acetate. M.P. 228-230 C.

(d) The solution of 2 g. of 16-chloromethylene-4-pregnene-l1/3,17a,21-triol-3,ZO-dione-Zl-acetate in 60 ml. of tetrahydrofuran is refluxed for 12 hours with 1.58 g. of chloranil. The reaction mixture is diluted with water and extracted with chloroform. The combined chloroform extracts are Washed with sodium hydroxide (2 N) and with water. Upon evaporation, the 16-chloromethy1- ene-4,6-pregnadiene 11p,17a,21 trial-3,20 dione 21- acetate crystallizes with methanol.

(e) As described in Example 10g, the l 6-chloromethylene- 4,6 pregnadiene 11 B,170:,2l-triol-3,20-dione-21- acetate is saponified to form 16'-chloromethylene-4,6- pregnadiene-11B,17a21-triol-3,20 dione. M.P. 206, (00;, +26 (dioxane), A 282.5 m

El? 689 (ethanol) (1) According to the procedure set forth in Example 112;, the 16-chloromethylene-4,6-pregnadiene-11fl,17a,21- triol-3,20-dione is dehydrogenated to form 16-chloromethylene 1,4,6 pregnatriene 11;3,17a,2l triol 3,20- dione-21-acetate.

Ellm. 350 (ethanol) Example 18 The procedure of Example 17 is applied identically to 165 fluoromethyl-16a,l7a-oxido-progesterone to prepare 16 fluoromethylene- 1,4,6-pregnatriene-1 1 3, 17a,2 l-triol- 3,20-dione. A 220, 254, 298 mp,

Effg 343, 267, 342

Example 19 (a) According to the methods given in Examples a to 10e, the 16-fluoromethylene-1l-epi-hydrocortisone-ZI- acetate is prepared from 16,8-fiuoromethyl-l6a,17a-0xidoprogesterone. k 241 m (b) The 16-fluoromethylene-1l-epi-hydrocortisone-Zlacetate is dissolved in 25 ml. of chloroform and 25 ml. of pyridine. The solution is cooled to 0 C. and 7 g. of p-toluenesulfonic acid are added with stirring. The mixture is stirred for another 2 hours at 0 C. and is allowed to stand overnight at room temperature. Then it is poured into water and extracted several times with chloroform. The chloroform extracts are neutralized and dried. Upon evaporation, the 16-fluoromethylene-1 1- epi-hydrocortisone-ll-tosylate-21-acetate is recrystallized from methanol.

The ester thus obtained is dissolved in 75 ml. of glacial acetic acid and refluxed for 30 minutes with 9 g. of anhydrous sodium acetate. The mixture is poured into 500 ml. of water. The precipitated 16-fluoromethylene- 4,9(11) pregnadiene-17a,21-diol-3,20-dione2l-acetate is filtered oil and recrystallized from ethyl acetate. 239 mp,

(c) 7.8 g. of 16 fluoromethylene 4,9(11)-pregnadiene-17a,21-diol-3,20 dione 21 acetate are dissolved in 315 ml. of dioxane and 40 ml. of water. After addition of 4.55 g. of N-bromosuccinimide and 1.68 ml. of perchloric acid (70%), the mixture is allowed to stand for 1 hour at room temperature. Then it is poured into water. The precipitated 16-fluoromethylene-9a-bromohydrocortisone-21-actate is filtered off, Washed with water and dried.

(d) The crude 16 fluoromethylene-9a bromo-hydrocortisone-Zl-acetate is dissolved in 450 ml. of ethanol and refluxed for 2 hours with 19 g. of potassium acetate.

The mixture is poured into water and the obtained emulof a mixture of 4.0 ml. oftetrahydrofuran, ml. of chloroform and 25 g. of hydrogenfluoride.

The reaction mixture is allowed to stand for 4 hours at and for 4 hours at 0. The solution is poured into a solution of NaHCO The steroid is extracted with chloroform.

Uponfevaporation, the 90c fluoro-16-fluoromethylenehydrocortisone-2l-acetate is recrystallized from acetone. max 9 l,

nit... 379

(f) 9a fluoro-l6-fluoromethylene-hydrocortisone-acetate is saponified according to Example 10g, to prepare 9a-fluoro-16-fluoromethylene-hydrocortisone.

(g) According to the method described in Example lle the 9a-fluoro-16-fluoromethylene hydrooortisone is dehydrogenated by the action of Bacillus sphaericus to form 9a-fiuoro-16-fluoromethylene prednisolone. A 242 mp,

ill... 4 13 Example 20 According to the method described in Example 19, the 9a-fluoro-16-ehloromethylene prednisolone is prepared from 165 chloromethyl 16a,17a oxido-progesterone. mart 242 i El tm. 402 Example 21 (a) According to the method described in Example 1a, the 60: methyl 16 fluoromethylene 17a hydroxyprogesterone is obtained from 6a-methy1-16-fluoromethyl- 16oz,170c-0Xld0-P10g68t610116.

(b) According to the method of Example 1b, the 600- methyl 16 fluoromethylene 17cc hydroxy progesterone is esterified to prepare 6amethyl-16-fluorometh ylene-17a-acetoxy-progesterone. A 240 mp,

(c) 5 g. of 16a-methyl-16-fluoromethylene-17a-acetoxy-progesterone are refluxed for 7 hours with m1. of methylethylketone and 7 g. of chloranil. Upon cooling, the solution is poured into water and extracted with chloroform. The chloroform extract is washed subsequently with water, aqueous sodium hydroxide (1%) and again water and is dried with sodium sulfate. Upon evaporation, the 60: methyl 16 fluoromethylene 4,6- pregnadiene-17a-ol-3,20-dione-17-acetate is crystallized from methanol. A 289-290 mg,

ll... 605 Example 22 (a) 8.5 g. of 16-fluoromethylene-4-pregnene 1113,17a, 21-triol-3,20-dione-21-acetate obtained according to Example 12d are refluxed for 7 hours with 335 ml. of tert. butanol and 59 g. of chloranil. The solution is concentrated to a volume of 100 ml. and extracted exhaustedly with chloroform upon addition of 380 ml. of water. The combined chloroform extracts are treated with ice cooled aqueous sodium hydroxide, washed with water to neutrality and concentrated under reduced pressure. The residue is dissolved in 25 ml. of a mixture containing equal volumes of benzene and of chloroform and chromatographed through 370 g. of florisil. The column is eluated with benzene/ chloroform (1:1). The eluates 20 to 50, each of 200 ml., are combined and concentrated. The 16 fluoromethylene 4,6 pregnadiene 11,8,17a,2ltriol-3,20-dione-21-acetate is recrystallized from ethyl acetate. A 285 me,

ill... 591

(b) 5.8 g. of 16-fluoromethylene-4,6-pregnadiene-11,8, 17a,21-triol-3,20-dione-2l-acetate are dissolved in .ml. of methanol and refluxed for 14 minutes upon addi- (c According to the method. described in Example 10h, 5 g. of 16-fluoromethylene 4,6-pregnadiene-11,3,17a, 21-triol-3,20-dione are dehydrogenated whereby the 16- fluoromethylene 1,4,6 pregnatriene ll 6,17a,21 triol- 3,20-dione is obtained. A 219, 255, 297 mp,

Ein 329, 245, 325

According to the method described in Example lle 5 g. of 16-tluoromethylene-4,G-pregnadiene-11,6,17a, 21triol-3,20-dione are dehydrogenated within 22 hours. The obtained 1S-fluoromethylene-l,4,6-pregnatriene-11B, 17a,21-t1iol-3,20.-dione is recrystallized from ethyl acetate. A 219, 255, 297 my;

EL 329, 245, 325 Example 23 (a) 1.3 g. of 6-Ch1OI0 IGfi-flUOI'OfllCIhYl-l60:,1701-0Xid0- 4,6-pregnadiene-3,20-dione are dissolved in 40 m1. of dioxane and 40 ml. of ether. After addition of 5 ml. of a solution of hydrogen bromide-in ether the mixture is refluxed for 45 minutes. The solution is concentrated and poured into water. The 6-chloro-16-fluoromethylene-4,6-pregnadiene-17a-o1-3,20-dione is recrystallized from acetone. A 284 m (b) According to the method described in Example 1b, the 6-chloro-16-fluoromethylene-4,6-pregnadiene-17ao1-3,20-dione is acetylated to form 6-chloro-16fluoromethylene 4,6 pregnadiene 17o: o1 3,20 dione 17- acetate. A 284-285 mp,

The corresponding 16-chloromethylene compound is ob taincd when using as starting material 6-chloro-l6fi-chloromethyl-16e,17-oxido-4,6-pregnadiene-3,20dione.

Example 24 terone are dissolved in 134 m1. of a mixture containing equal amounts of ether and tetrahydrofuran and refluxed for 1 hour upon addition of ml. of hydrogen bromide in ether (8% solution). The mixture is concentrated ,Eii 628 (ethanol) Example 25 A variety of esters of'the compounds prepared in accordance with the procedures oi the preceding examples are prepared by treating the free cohols with acylating agents by conventional methods. Th s, the hydroxyl group in the 21-position of the following compounds is esterified:

16-fluoromethylene-prednisolone IS-chloromethylene-prednisolone l6-fluoromethylene-prednisolone 6a-methyl-l6-fluoromethylene-prednisoione fia-methyl-l6-chloromethylene-prednisolone Six-fluoro-l6-fluoromethylene-prednisolone 9a-fiuoro-lfi-fiuoromethylene-prednisolone 6-dehydro-l6dlu oromethylene-prednisolone G-dehydro-lfi-fluoromethylene-hydrocortisone.

The esters include the phosphate and the sodium salt thereof; the hemisulfate and the sodium salt thereof; the

14 hemisuccinate and the sodium salt thereof; the diethylaminoaoetate and the hydrochloride thereof; the acetate; the tertbutylacetate; and the trimethylacetate and metasuliobenzoate.

Likewise, the 17t1-8CCt3-t65 and l'ia-capronates of 16- fluoromethylene-l7at-hydroxy-progesterone, 6a-methyl-l6- fluoromethylene-l7a-hydroxy-progesterone, 6-dehydro-16- fiuoromethylene-17a-hydroxy-progesterone, and fi-chloro- 6-dehydro-17a-hydroxy-progesterone are prepared by treatment with the corresponding acylating agents in the usual manner.

What we claim is:

1. A compound selected from the group consisting of Rt and the A A and A -derivatives thereof, wherein R is a member of the group consisting of hydrogen and the acid moiety of an aliphatic carboxylic acid containing up to 8 carbon atoms;

R is a member of the group consisting of a-H, p-OH;

H, H; and keto;

R is a member of the group consisting of hydrogen,

methyl, chlorine and fluorine;

X is a member of the group consisting of chlorine and fluorine; Y is a member of the group consisting of hydrogen and fluorine.

2. 6a-fluoro-l6-fluoromethylene-prednisolone.

3. 6a-fluoro-1G-chloromethylenc-prednisolone.

4. G-dehydro-lfi-fluoromethylene-prednisolone.

5. G-dehydro-IG-chIoromethyIeneprednisolone.

6. 6-dehydro-l6-fluoromethylene-hydrocortisone.

7. 1G-fluoromethylene-l'Ia-acetoxy-progesterone.

8. 6c: methyl 16 fluoromethylene 17 acetoxyprogesterone.

9. 6 dehydro 16 fluorometheylene 17a acetoxy progesterone.

10. 6 chloro 6 dehydro l6 fluoromethylene 17- acetoxy-progesterone.

11. In a process of manufacturing a member of the" group consisting of a compound of the formula and the A 3 and A -derivatives thereof wherein R is a member of the group consisting of hydrogen and a free and esterified hydroxyl group;

R is a member of the group consisting of hydrogen and the acid moiety of an aliphatic carboxylic acid containing up to 8 carbon atoms;

R is a member of the group consisting of 1-H, ,B-OH;

H, H; and keto;

R is a member of the group consisting of hydrogen,

methyl, chlorine and fluorine;

X is a member of the group consisting of chlorine and fluorine; and

3,161,661 15 16 Y is a member of the group consisting of hydrogen and of an inert organic solvent with hydrogen bromide, said fluorine, inert organic solvent being a mixture of ether and dioxane. the step which comprises reacting a member of the group 12. The process of claim 11 wherein the ratio by volconsisting of a compound of the formula ume of ether to dioxane is approximately 1: 1.

5 iR! References Cited by the Examiner UNITED STATES PATENTS 2,882,282 4/59 Agnello et a1. 260-3973 1 2,891,079 6/59 Dodson et al. 260397.4 3,065,239 11/62 Wendlcr et a1. 260397.45

OTHER REFERENCES Chemical and Engineering News, September 16, 1957, 15 pp. 66-67.

1'2 LEWIS GO'I'I'S, Primary Examiner.

and the A A and A -derivatives thereof in the presence LIEBMAN' Examiner 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 